1 research outputs found
Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability
The free fatty acid receptor 1 (FFA1, also known as GPR40)
mediates
enhancement of glucose-stimulated insulin secretion and is emerging
as a new target for the treatment of type 2 diabetes. Several FFA1
agonists are known, but the majority of these suffer from high lipophilicity.
We have previously reported the FFA1 agonist <b>3</b> (TUG-424).
We here describe the continued structure–activity exploration
and optimization of this compound series, leading to the discovery
of the more potent agonist <b>40</b>, a compound with low lipophilicity,
excellent in vitro metabolic stability and permeability, complete
oral bioavailability, and appreciable efficacy on glucose tolerance
in mice